1. Field of Invention
The invention relates generally to devices for testing of biologics. More particularly, this invention relates to micro-organ devices and methods for fabricating and using such devices.
2. Discussion of the Related Art
Testing of pharmaceuticals and biological compounds in humans or in animals is not always possible, at least not in the early stage. Moreover, while in vivo animal studies can provide data more relevant to human responses, animal tests are expensive, labor-intensive, and time consuming. Accordingly, sometimes decisions need to be made based on in vitro data. However, extrapolating in vitro data (e.g., cell culture data) to the in vivo relevant conditions is often difficult. Although pharmacokinetic principles can be used to derive some conclusions, this approach has limitations due to various reasons.
For example, cell cultures under traditional assay conditions may not function in the same ways as cells would in natural settings because the communication and interactions between different tissues and organs are absent. In culture, cells are typically grown at the bottom of chambers or wells. These systems may have unrealistically high liquid-to-cell ratios. Even if the cells are grown on microcarrier beads, which more closely resemble physiological conditions, they still may not mimic physiological conditions accurately enough to provide reliable data.
Additionally, while controlling the spatial orientation of cells having a cell-cell interaction in a co-culture would improve traditional cell culture methods, the cell-cell interactions between different cell types do not always allow proper interactions between different cell types. In humans and animals, the liver plays an important role in the metabolism and bioavailability of pharmaceuticals and biological compounds. Consequently, methods of predicting human response from in vitro cell culture assays are complicated, and systems or devices of the related art designed to replicate in vivo organs or systems of humans or animals have not performed quite as predicted.
Accordingly, scientists with ordinary skill in the art related to this subject matter have recognized a long-felt need for in vitro organ or system models that can mimic the in vivo organs or systems in humans or animals. The related art includes U.S. Pat. No. 5,612,188 issued to Shuler et al., which is hereby incorporated by reference. This patent discloses a multi-compartmental cell culture system comprising culture chambers, sensors, and pumps, but is a system operating on a large scale, so the physiological parameters vary considerably from those found in an in vivo situation.
The related art also includes U.S. Pat. No. 7,288,405 by Shuler et al., which is incorporated herein by reference. This reference discloses in vitro microscale cell culture analog devices that permit cells to be maintained in vitro under conditions similar to those found in vivo. The microscale culture device comprises a fluidic network of channels segregated into discrete but interconnected chambers. The specific chamber geometry is designed to provide cellular interactions, liquid flow, and liquid residence parameters that correlate with those found for the corresponding cells, tissues, or organs in vivo. Fluidics are designed to accurately represent primary elements of the circulatory or lymphatic systems. In one embodiment, the components are integrated into a chip format. The design and validation of these geometries is based on a physiological-based pharmacokinetic (PBPK) model, a mathematical model that represents the body as interconnected compartments representing different tissues.
Similarly, U.S. Patent Application Publication No. 2003/0152909 A1 discloses micro-organ cultures which include isolated populations of cells having specific characteristics. These micro-organ cultures have the ability to be maintained in culture for relatively long periods of time, as well as the preservation of an organ micro-architecture which facilitates, for example, cell-cell and cell-matrix interactions analogous to those in the source organ.
These organ models of the related art demonstrate the advantages of in vitro systems for pharmaceutical or biological compounds testing. However, the related art approaches rely on directly placing the cells in the chamber or seeding the cells and allowing them to grow in the chamber. These approaches do not always provide reproducible organs. Therefore, there remains a need for in vitro organ devices, and methods for their preparation, which can mimic the in viva organs or systems in humans and animals.